Ultrasound has attracted considerable attention not only as a diagnostic imaging modality but also as a physical trigger for drug delivery system (DDS). Ultrasound irradiation applied in combination with gas-filled bubbles can induce cavitation and transiently increase the permeability of cellular membranes, thereby enhancing the intracellular delivery of therapeutic molecules. Our research group has developed ultrasound-responsive gas-containing lipid nanoparticles, initially termed bubble liposomes (BLs) and later referred to as nanobubbles (NBs), as carriers for nucleic acid delivery. Early studies indicated that BLs facilitated the efficient cytoplasmic delivery of small interfering RNA under ultrasound irradiation. Subsequent investigations expanded the platform to include diverse nucleic acids, including plasmid DNA and microRNA, and revealed therapeutic efficacy in disease models such as hindlimb ischemia. Further developments include strategies for brain-targeted gene delivery mediated via blood-brain barrier modulation and the design of stable anionic NBs with the capacity to load nucleic acids via cationic intermediates. More recently, polysaccharide-coated NBs and microfluidic preparatory methods have been assessed with a view to improving delivery performance and particle uniformity. These advances highlight the potential utility of nucleic acid-loaded NBs as theranostic platforms for the integration of ultrasound imaging and gene delivery. The continued development of this technology may contribute to the advancement of next-generation ultrasound-mediated DDS.
